• Ang Zhao, Zhanjie Zhang, Yanfen Zhou, Xin Li, Xiaotian Li, Bo Ma, and Qi Zhang.
• School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, People's Republic of China.
• Phytomedicine. 2020 Apr 1; 69: 153183.

BackgroundOsteosarcoma (OS) is a significant threat to the lives of children and young adults. Although neoadjuvant chemotherapy is the first choice of treatment for OS, it is limited by serious side-effects and cancer metastasis. β-Elemonic acid (β-EA), an active component extracted from Boswellia carterii Birdw., has been reported to exhibit potential anti-inflammatory and anticancer activities. However, the anti-tumor effects and underlying mechanisms on OS as well as pharmacokinetic characteristics of β-EA remain unknown.PurposeThis study was aimed to investigating the anti-tumor effects of β-EA on human OS, the underlying mechanisms, and the pharmacokinetic and tissue distribution characteristics.Study Design And MethodsCell viability and colony formation assays were performed to determine the effect of β-EA cell on cell proliferation. Apoptosis rates, mitochondrial membrane potential and cell cycle features were analyzed by flow cytometry. qRT-PCR, Western blot, immunofluorescence and immunohistochemical assays were conducted to evaluate the expression levels of genes or proteins related to the pathways affected by β-EA in vitro and in vivo. Cell migration and invasion were evaluated in wound healing and Transwell chamber assays. The effects and pharmacokinetic characteristics of β-EA in vivo were evaluated by analyzing tumor suppression, pharmacokinetics and tissue distribution.ResultsExplorations indicated that endoplasmic reticulum (ER) stress conditions provoked by β-EA activated the PERK/eIF2α/ATF4 branch of the unfolded protein reaction (UPR), stimulating C/EBP homologous protein (CHOP)-regulated apoptosis and inducing Ca2+ leakage leading to caspase-dependent apoptosis. Furthermore, β-EA induced G0/G1 cell cycle arrest and inhibited metastasis of HOS and 143B cells by attenuating Wnt/β-catenin signaling effects, which included decreased levels of p-Akt(Ser473), p-Gsk3β (Ser9), Wnt/β-catenin target genes (c-Myc and CyclinD1) along with a decline in nuclear β-catenin accumulation. The fast absorption, short elimination half-life, and linear pharmacokinetic characteristics of β-EA were also revealed. The distribution of β-EA was detected in the tumor and bone tissues.ConclusionsOverall, both in vitro and in vivo investigations showed the potential of β-EA for the treatment of human OS. The pharmacokinetic profile and considerable distribution in the tumor and bone tissues warrant further preclinical or even clinical studies.Copyright © 2020 Elsevier GmbH. All rights reserved.

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